Benzodioxan amino alcohols



' ration of salts from bases.

Patented May 1, 1951 UNITED STATES PATENT OFFICE 2,551,013" BENZODIOXANAMINO ALCOHOLS 1... f

James F. Kerwin, Philadelphia, Pa., assigno'r to Smith, Kline & FrenchLaboratories, Philadelphia, 2a., a corporation of Pennsylvania NoDrawing. Application May 28, 1949, SeriaLNo. 96,159

5 Claims. (01. 260-33 a This invention relates to certain new chemicalcompounds which more particularly comprise certain benzodioxan aminoalcohols.

The benzodioxan amino alcohols contemplated The benzodioxan aminoalcohols accordingto this in 'ventionare prepared, as indicated above byreaction of-2 chloromethylbenzodioxan, or 2 bromomethylbenzodioxan, withan N-monosub-j by this invention have been found to have utility 5stituted amino, alcohol "or the structure exm as intermediates inorganic syntheses and by way of example as intermediates for use in thepreparation of certain benzodioxan derivatives which possessphysiological properties. The compounds of this invention have thefollowing general formula:

in which Z is selected from the group consisting of lower alkyl, loweralkenyl and benzyl.

It will be understood thatthe inorganic and organic addition salts ofthe several benzodioxan amino alcohols formed with. inorganic andorganic acids, as, for example, sulfuric, hydrochloric, phospheric,sulfamic, tartaric, glycolic, succinic, hydrobromic, etc., arecontemplated as a part of and included in this invention. The severalsalts will be respectively made apparent from the above general formulaeby the simple addition to the amino group of an organic or an inorganicacid radical.

The inorganic and organic salts of the several compounds will be readilyprepared from the benzodioxan aminoalcohols and recovered by usual andwell known procedure for the prepaw In the following description ofprocedure for::

the preparation of the benzodioxan amino 311C015.

hols according to this invention and specific examples of such alcohols,it will be understood that Where formulae are set out, the substituent Zwill be as given formulae above.

All of the several benzodioxan amino alcohols contemplated by thisinvention will be prepared by a process which will be made apparent bythe following scheme:

I OH,

HC.Hr-X

plified above. The reaction is advantageously carried out in an inertsolvent, such as dry xylene, and the base obtainedis'usually purified bycrystallization as the hydrochloride or other addition salt, althoughthe free base may be isolated as such by distilling oil the solvent. Itis also advantageous to employ an excess of the N-,. monosubstitutedamino alcohol to remove the hydrogen halide formed as a by-product ofthe reaction. When the ben'zodioxanamino alcohol is obtained as a salt,the free bas will readily. be obtained by usual and'well'knownprocedures as, for example. by addition of a strong base assodium hydroxide, to 'a'cold aqueous solution; of "the salt andextraction of the. free base. into a solvent such as ether or benzene,and distilling off the solvent. f p v In the preparation of thebenzodioxan amino. alcohol as described above, an N-monosubstitutedamino alcohol, corresponding to the l en"- zodioxan amino alcohol to beproduced,' [and which is well known or obviously'prepared, willi be usedfor reaction with 2-chloromethylbenzodioxan, or2-bromomethylbenzodioxan, Thus, by way of illustration the followingN-monosubstituted amino alcohols may be used:

2-methylaminoethanol 2-ethylaminoethanol 2-allylaminoethanolZ-benzylaminoethanol '3.

2-(cyclohexylaminoethanol) above with reference to the i2-isopropylaminoethanol..U 2- (n-heptylaminolethanol 2-(cyclohexylisopropylamino) ethanol accomplished by usual and well knownprocedure for replacing a hydroxyl group with halogen.

Where in the above described procedure the desired benzodioxanp-haloethylamine is obtained in the form of a salt; as thehydrochloride, or other organic or --inorganic- 'saltthrough the use ofan organic or inorganic salt of the benzodioxan amino alcohol as anintermediate, the free base will readily be obtained by addition of astrong base to a cold aqueous solution of the benzodioxanc-haloethylamine salt and extraction of the free base into an organicsolvent such as ether or benzene.

The following examples will more specifically illustrate the benzodioxanamino alcohols. according to this invention and procedure for theirpreparation and, in addition, use thereof as intermediates in thepreparation of benzodioxan derivatives.

EXAlVIPLE 1 2- [N- (fihydroxyethyl) -N-ethylaminomethyll benzodioxan Forthe preparation of this compound, a solution of 20.2 g.2'-chloromethylbenzodioxan, 19.6 g. of ethylaminoethanol and 50 m1, ofdry xylene is refluxed for thirteen and one-half hours. The cooledsolution is diluted with ether and ethylaminoethanol hydrochloride,formed as a byproduct of the reaction, is removed by filtration.-

The filtrate is Washed repeatedly with water, dried and treated withanhydrous hydrogen chloride. ether mixture, the hydrochloride ofZ-[N-(fihydroxyethyl) -N-ethylaminomethy1] benzodioxan. produced meltsat 126-127.5 C. The free base will be obtained as described above.

I As exemplifying use of the above product as an intermediate, asolution of 9.5 g. of thionyl chloride in 50 ml. of dry chloroform isadded to a sus-r CaHs EXAMPLE 2 2 [N- (fl-hydromyethyl)-N-benzylaminomethyll benzodioxan hydrochloride For the preparation ofthis compound a solution of 21.7 g. of 2-chloromethylbenzodioxan; 35.8

g. of benzylaminoethanol and ml. of dry xylene isrefluxed for 20 hours,cooled and dilutedwith ether. Benzylaminoethanol hydrochloride isfiltered off, the filtrate is washed with water and dried. Whenanhydrous hydrogen chloride is introduced into the dried solution, thehydrochloride of 2- [N-(fi-hydroxyethyl) -N benzyl-aminomethyl]benzodioxan is formed. After recrystal liaation from alcohol-ether, itmelts at 1345+ 13 7.5 C. The free base will be obtained as de-.

scribed above.

After recrystallization from an alcohol-- amine hydrochloride whichmelts at 148-151.5 C. and has the structure:

The following are among the many other com- "pounds embraced by thepresent invention and, by choosing the proper N-substituted aminoalcohoLmay be prepared by the method described above, and will serve asintermediates for the preparationof the corresponding benzodioxanderivatives as'described above.

EXAMPLE 3 2 [N- (p-hydroxyethyl) -N-methylaminomethyl] benzodioxanhaving the structure:

This compound is prepared by the procedure of Example 1, using anequivalent amount of meth- ,The amino alcohol hydrochloride whentreated",

with thionyl chloride in the same manner as de scribed in. Example lwill yield the fl-chlwethyk ylaminoethanol instead of ethylaminoethanol.The compound can also be recovered as the hydrochloride as described inExample 1.

EXAMPLE 4 2- [N- (fl-hydroxyethyl) -N-ally1aminomethyl] benzodioxanhaving the structure:

' This compound will be prepared by reacting 2-chloromethylbenzodioxanand two molar equivalents of 2-allylaminoethanol by the method describedunder Example 1, and can be recovered as the hydrochloride if desired.

EXAMPLE 5 2 [N (p2 hydroxyethyl) N cyclohexylaminomethyl] benzodioxanhaving the structure:

C'Hg JH-CHr-N-CHr-CHr-OH 0 H on, cH,

Hg CH: O I a This compound, asthe'free base or hydrochloride, will beprepared -;by the method described under- Example usingcyclohexylaminoethanol in place of ethylaminoethanol.

EXAMPLE 6 2 [N 3 hydroxyethyl) N cyclohexylisopropylaminomethyl]benzodioxan having the structure:

This compound, as the free base or hydrobromide, will be prepared byreaction of 2-bromomethylbenzodioxan with 2-(cyclohexylisopropylamino)ethanol in xylene solution as described under Example 2.

2-(cyclohexylisopropylamino) ethanol is obtained by reductive aminationof cyclohexylacetone with ethanolamine in alcohol solution in thepresence of platinum catalyst. 2-(cyclohexy1isopropylamino) ethanol isrecovered by distillation, B. P. 154-158 C. at 2mm. Hg pressure.

From the above pecific examples of the several different types ofcompounds contemplated by this invention, the specific structure of eachand all of the several compounds within the general formulae given andspecific exemplification of each and every one of the compounds withinthe general formula is had by the simple expedient of substituting for Zin the general formulae the substituents given therefor.

From the foregoing generaland specific disclosure of procedure for thepreparation of the compound and salts thereof contemplated by thisinvention, it is apparent to those skilled in the art that all thecompounds and salts will be prepared by the procedure described andexemplified by the mere use of the reagents corresponding to anyparticular compound desired, the reagents for any particular compoundbeing either well known or prepared by the procedure indicated andaffording no problem to the chemist.

While in the foregoing examples the products in accordance with thisinvention are exemplified by their free bases and hydrochloride salts,the several examples will serve as specific examples of other organicand inorganic salts by the mere inclusion of the desired acid radical inthe formula for the free base. As has been indi- 55 cated, where thecompounds are obtained as salts, the free bases will be obtained fromthe salts by usual and well known procedure comprising treatment with aninorganic base such as sodium carbonate, sodium hydroxide, or the 60like.

The above general formula will serve as specifically exemplifyin all theseveral compounds embraced thereby by a mere substitution in the formulafor Z of the substituents given therefor 65 Number in connection withthe formula i. e., a mere 6 mechanical exercise, hence thisspecification is not rendered voluminous by the setting forth offormulae for each and every compound contemplated and each and everysalt thereof, respectively, such being quiteunnecessary in view of thedisclosure which makes the structure of each and all thereof entirelyclear to those skilled in the art.

This application is a continuation-in-part of application Serial No.65,507, filed December 15, 1948.

What is claimed is:

1. Benzodioxan derivatives having the following structure:

cH, JHCH1NCH -CH -OH in which Z is selected from the group consisting oflower alkyl, lower alkenyl and benzyl; and organic and inorganic saltsof said compounds.

2. A compound having the following structure:

dH-oH,N-oH, oH,-oH-Hc1 3. A compound having the following structure:

4. A compound having the following structure:

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date 2,056,046 Fourneau Sept. 29, 1936

1. BENZODIOXAN DERIVATIVES HAVING THE FOLLOWING STRUCTURE: